Lymphocyte development: integration of DNA damage response signaling.
Lymphocyte development: integration of DNA damage response signaling.
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DOI：
10.1016/b978-0-12-394300-2.00006-5
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发表时间：
2012
影响因子：
--
通讯作者：
Sleckman BP
中科院分区：
文献类型：
--
作者：
Bednarski JJ;Sleckman BP
淋巴细胞在发育成成熟的B和T细胞时经历功能上不连续的阶段。这种发展是由来自各种不同细胞表面受体的线索指导的。为了完成发育，所有淋巴细胞必须表达功能性非自身反应性异源二聚体抗原受体。编码抗原受体链的基因通过V（D）J重组过程组装，这是一种通过DNA双链断裂（DSB）中间体进行的反应。这些DSB由G1期发育淋巴细胞中的RAG内切核酸酶产生，并激活共济失调-毛细血管扩张突变（ATM），这是一种协调细胞DSB反应的激酶。典型的DNA损伤反应包括细胞周期停滞、DNA断裂修复和当DSB未被修复时的细胞凋亡。然而，最近的研究表明，ATM激活响应RAG DSB也调节转录程序，包括许多基因在典型的DNA损伤反应中没有已知的功能。相反，这些基因具有对淋巴细胞发育重要的活性。在这里，这些研究结果和更广泛的概念，生理DNA DSB启动的信号提供的线索，调节细胞类型的特定过程和功能进行了讨论。
Lymphocytes traverse functionally discrete stages as they develop into mature B and T cells. This development is directed by cues from a variety of different cell surface receptors. To complete development, all lymphocytes must express a functional nonautoreactive heterodimeric antigen receptor. The genes that encode antigen receptor chains are assembled through the process of V(D)J recombination, a reaction that proceeds through DNA double-stranded break (DSB) intermediates. These DSBs are generated by the RAG endonuclease in G1-phase developing lymphocytes and activate ataxia-telangiectasia mutated (ATM), the kinase that orchestrates cellular DSB responses. The canonical DNA damage response includes cell cycle arrest, DNA break repair, and apoptosis of cells when DSBs are not repaired. However, recent studies have demonstrated that ATM activation in response to RAG DSBs also regulates a transcriptional program including many genes with no known function in canonical DNA damage responses. Rather, these genes have activities that would be important for lymphocyte development. Here, these findings and the broader concept that signals initiated by physiologic DNA DSBs provide cues that regulate cell type-specific processes and functions are discussed.